Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease

Heather Wilson; Gennaro Pagano; Edoardo Rosario de Natale; Ayla Mansur; Silvia Paola Caminiti; Sotirios Polychronis; Lefkos T. Middleton; Geraint Price; Karl F. Schmidt; Roger N. Gunn; Eugenii A. Rabiner; Marios Politis

doi:10.1002/mds.28064

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease

Heather Wilson, Gennaro Pagano, Edoardo Rosario de Natale, Ayla Mansur, Silvia Paola Caminiti, Sotirios Polychronis, Lefkos T. Middleton, Geraint Price, Karl F. Schmidt, Roger N. Gunn, Eugenii A. Rabiner, Marios Politis^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [¹¹C]UCB-J, [¹¹C]SA-4503, and [¹⁸F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. Results: Reduced [¹¹C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [¹¹C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [¹¹C]SA-4503 and [¹⁸F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [¹¹C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression.

Original language	English
Pages (from-to)	1416-1427
Number of pages	12
Journal	Movement Disorders
Volume	35
Issue number	8
DOIs	https://doi.org/10.1002/mds.28064
Publication status	Published - 1 Aug 2020

Keywords

mitochondria
molecular biomarkers
Parkinson's disease
positron emission tomography
synaptic vesicle protein

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10.1002/mds.28064

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@article{bda7194fea5341ce9790021cb4d50bf7,

title = "Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease",

abstract = "Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB-J, [11C]SA-4503, and [18F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. Results: Reduced [11C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA-4503 and [18F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression.",

keywords = "mitochondria, molecular biomarkers, Parkinson's disease, positron emission tomography, synaptic vesicle protein",

author = "Heather Wilson and Gennaro Pagano and {de Natale}, {Edoardo Rosario} and Ayla Mansur and Caminiti, {Silvia Paola} and Sotirios Polychronis and Middleton, {Lefkos T.} and Geraint Price and Schmidt, {Karl F.} and Gunn, {Roger N.} and Rabiner, {Eugenii A.} and Marios Politis",

year = "2020",

month = aug,

day = "1",

doi = "10.1002/mds.28064",

language = "English",

volume = "35",

pages = "1416--1427",

journal = "Movement disorders : official journal of the Movement Disorder Society",

issn = "0885-3185",

publisher = "Wiley",

number = "8",

}

TY - JOUR

T1 - Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease

AU - Wilson, Heather

AU - Pagano, Gennaro

AU - de Natale, Edoardo Rosario

AU - Mansur, Ayla

AU - Caminiti, Silvia Paola

AU - Polychronis, Sotirios

AU - Middleton, Lefkos T.

AU - Price, Geraint

AU - Schmidt, Karl F.

AU - Gunn, Roger N.

AU - Rabiner, Eugenii A.

AU - Politis, Marios

PY - 2020/8/1

Y1 - 2020/8/1

N2 - Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB-J, [11C]SA-4503, and [18F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. Results: Reduced [11C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA-4503 and [18F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression.

AB - Background: Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross-sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug-naive PD patients. Methods: Twelve early drug-naive PD patients and 16 healthy controls underwent a 3-Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB-J, [11C]SA-4503, and [18F]BCPP-EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1-year follow-up assessments. Results: Reduced [11C]UCB-J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug-naive PD patients compared with healthy controls. [11C]UCB-J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA-4503 and [18F]BCPP-EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB-J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow-up compared with baseline. Conclusions: Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug-naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow-up will determine the validity of these PET markers to track disease progression.

KW - mitochondria

KW - molecular biomarkers

KW - Parkinson's disease

KW - positron emission tomography

KW - synaptic vesicle protein

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U2 - 10.1002/mds.28064

DO - 10.1002/mds.28064

M3 - Article

AN - SCOPUS:85084008918

SN - 0885-3185

VL - 35

SP - 1416

EP - 1427

JO - Movement disorders : official journal of the Movement Disorder Society

JF - Movement disorders : official journal of the Movement Disorder Society

IS - 8

ER -

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease

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Keywords

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